Attenuation of Aluminum Chloride-Induced Neuroinflammation and Caspase Activation Through the AKT/GSK-3β Pathway by Hesperidin in Wistar Rats

Abstract

Hesperidin, a flavanoglycone abundantly present in citrus fruits, is reported to have antioxidant, anti-inflammatory, and neuroprotective properties. Previous reports from our laboratory indicated the neuroprotective effect of hesperidin against aluminum chloride (AlCl)-induced memory loss, acetylcholine esterase hyperactivity, oxidative stress, and enhanced expression of amyloid β protein biosynthesis-related markers. However, their role on AlCl-induced inflammation, caspase activation, Tau pathology, altered Akt/GSK 3β signaling pathway, and Aβ clearance marker has not yet been fully elucidated. Intraperitonial injection of AlCl (100 mg/kg body weight) for 60 days significantly elevated the expressions of insulin-degrading enzyme (IDE), cyclin-dependent kinase 5 (CDK 5), and phosphoTau (pTau); inflammatory markers such as glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), NF-kB, cyclooxygenase-2 (COX-2), interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS); and apoptotic markers including cytosolic cytochrome c (cyto c), caspase-3, caspase-8, and caspase-9, and lowered expressions of mitochondrial cyto c, phospho-Akt (pAkt) and phospho-glycogen synthase kinase-3β (pGSK-3β) in the hippocampus and cortex. Co-administration of hesperidin to AlCl rats for 60 days significantly ameliorated the aluminum-induced pathological changes. The behavioral studies also supported the above findings. Our results imply that treatment with hesperidin might be a potent option for treating the symptoms of cognitive impairment in Alzheimer's disease by targeting its most prominent hallmarks.

The Protective Effects of Melatonin on Aluminum-Induced Hepatotoxicity and Nephrotoxicity in Rats

“…The observed morphological lesions in the hepatic and renal tissues of AlCl 3 -intoxicated rats may explain the increased levels of the proinflammatory cytokines TNF- α and IL-1 β as compared with the CON group. The data of the present study agree with the results of Zhang et al [ 40 ], Justin-Thenmozhi et al [ 41 ], and Hosny et al [ 42 ], who found that Al exposure increased the levels of TNF- α and IL-1 β in the liver and kidney tissues of rats.…”

Inhibition of autophagy via activation of PI3K/Akt/mTOR pathway contributes to the protection of hesperidin against myocardial ischemia/reperfusion injury

“…Phosphorylated mTOR has been reported to protect against I/R injury by reducing autophagy and enhancing recovery in the heart ( 41 ). It has been reported that hesperidin activates the Akt pathway in a rat model of neuroinflammation induced by aluminum chloride ( 42 ). Saiprasad et al ( 43 ) also demonstrated that hesperidin regulates the PI3K/Akt/mTOR pathway in a mouse model of colon carcinogenesis.…”

Effect of Essential Oils from Ginger (Zingiber officinale) and Turmeric (Curcuma longa) Rhizomes on Some Inflammatory Biomarkers in Cadmium Induced Neurotoxicity in Rats

“…The production of amyloid beta proteins by β -secretase (BACE) and γ -secretase in frontal cortex and hippocampus has been linked to the pathogenesis of AD [ 2 ]. Several studies have established the relationship between neuroinflammation and AD linking the involvement of heavy metals [ 2 , 3 , 19 , 20 ].…”

“…Neuroinflammatory processes have been linked to the activation of three common cytokines namely; interleukin-6 (IL-6), interleukin-1 beta (IL-1 β ), and tumor necrosis factor alpha (TNF- α ) in the CNS [ 1 ]. Several heavy metals have been implicated in the role of neuroinflammation and Alzheimer's disease (AD) via formation of neurofibrillary tangles and amyloid-beta plaques [ 2 , 3 ].…”